Tau mis-splicing correlates with motor impairments and striatal dysfunction in a model of tauopathy

Abstract

Tauopathies are neurodegenerative diseases caused by the abnormal metabolism of the microtubule associated protein Tau, which is highly expressed in neurons and critically involved in microtubule dynamics. In the adult human brain, the alternative splicing of exon 10 in tau pre-mRNA produces equal amounts of protein isoforms with either three (3 R) or four (4 R) microtubule binding domains. Imbalance in the 3 R : 4 R tau ratio is associated with primary tauopathies that develop atypical parkinsonism, such as Progressive Supranuclear Palsy and Corticobasal Degeneration. Yet, the development of effective therapies for those pathologies is an unmet goal.

Here we report motor coordination impairments in the htau mouse model of tauopathy which bear abnormal 3 R : 4 R tau isoforms contents, and contrariwise to TauKO mice, are unresponsive to L-DOPA. Preclinical-PET imaging, array tomography and electrophysiological analyses pointed the dorsal striatum as the candidate structure mediating such phenotypes. Indeed, local modulation of tau isoforms by RNA trans-splicing in the striata of adult htau mice, prevented motor coordination deficits and restored basal neuronal firing. Together, these results constitute readout that abnormal striatal tau-isoforms contents might lead to parkinsonian-like phenotypes and provide proof of concept that modulation of tau mis-splicing could be a plausible disease-modifying therapy for some primary tauopathies.